The nuclear lamina, composed of A and B-type lamins, maintains nuclear morphology and functions as an anchoring platform for tethering chromatin T. Dechat et al. (2008) Genes Dev. 22, 832). Lamins interact with numerous chromatin-bound proteins and are also indirectly linked to the cytoskeleton, via transmembrane proteins including Nesprins and SUN proteins (M. Crisp et al. (2006) J. Cell Bio. 172, 41). Mutations in LMNA, which encodes Lamin A and C, cause a wide spectrum of human diseases known as laminopathies (H. J. Worman, G. Bonne (2007) Exp. Cell Res. 313, 2121). These include Emery-Dreifuss muscular dystrophy (AD-EDMD) (G. Bonne et al. (1999) Nat. Genet. 21, 285) and the severe accelerated-ageing disease Hutchinson Gilford Progeria Syndrome (HGPS) (A. De Sandre-Giovannoli et al. (2003) Science 300, 2055; M. Eriksson et al. (2003) Nature 423, 293). Deregulation of A-type lamins has also been observed in various human cancers, where they are aberrantly expressed or localized (J. L. Broers et al. (1993) Am. J. Pathol. 143, 211; S. F. Moss et al. (1999) Gut 45, 723; R. S. Venables et al. (2001) Br. J. Cancer 84, 512).
Lamin A/C depletion or LMNA mutations cause enlarged, misshapen nuclei associated with loss of global chromatin organization (G. Galiova et al. (2008) Eur. J. Cell Biol. 87, 291). The exact molecular causes for the broad range of clinical phenotypes associated with laminopathies, however, remain to be defined. While some of these pathologies might reflect the primary molecular defect in lamin disorganization causing cellular fragility (the “structural hypothesis”), many seem likely to result from downstream effects on chromatin structure, gene expression or additional nuclear processes such as replication, transcription and DNA repair (K. L. Wilson et al. (2001) Cell 104, 647). Interestingly, recent studies suggest that improving nuclear architecture of laminopathic cells can also ameliorate certain downstream defects in chromatin structure and other cellular processes, thus improving some disease-associated phenotypes (C. Y. Chen et al. (2012) Cell 149, 565; J. I. Toth et al. (2005) PNAS 102, 12873; M. Columbaro et al. (2005) Cell Mol. Life Sci. 62, 2669).
There is therefore a need to provide treatments which correct nuclear architecture defects and improve cellular fitness of laminopathic human cells, thereby treating laminopathies and premature ageing disorders.